16alpha-bromo- and 16alpha-iodopregnanes and process



United States Patent 3,189,623 16u-BROM0- ANT) Ida-TODOPREGNANE AND PROCESS Donald E. Ayer, Portage Township, Kalamazoo County, Mich, assignor to The Upjohn Company, Kalamazoo, Niich, a corporation of Delaware No Drawing. Filed Dec. 11, 1963, Ser. No. 329,865 18 Claims. (Cl. 269-3914) This invention relates to novel steroid compounds and is more particularly concerned with progestationally active 16a-bromo-fia-methylpregnanes, 16a-iodo-6a-methylpregnanes and intermediates for the production thereof, as Well as processes for the production thereof.

The novel products and the process of the production thereof can be illustratively represented as follows:

i if. f;

'---on OAc on or a l t Q5 22. I (ECU W m wherein Hal is a halogen atom selected from the group consisting of bromine and iodine and wherein Ac is the acyl radical of an organic carboxylic acid, particularly of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

The process of the novel invention comprises: treating a 16ec-halo-3B,17a-dihydroxy-6-methyl-5-pregnen-20-one (I) with an acylating agent selected from acyl bromides, acyl chlorides, and organic carboxylic acid anhydrides wherein the acyl group of the organic carboxylic acids is defined as hereinabove, to obtain the corresponding 160chalo-3B,l7u-diacyloxy-6-methyl5-pregnen-20-one (l1); subjecting this diacylate of Formula II to selective solvolysis to obtain the corresponding l6m-halo-3fi-hydroxy- 6-methyl-17-acyloXy-5-pregnen-20-one (III), and oxidizing the l7-monoester to obtain the corresponding 16ahalo-Ga-methyl-17a-acyloxyprogesterone (IV) (16a-halo- 6oz methyl-I7oc-hydroxy-4-pregnene-3,20-dione 17-acy1- ate).

The novel compounds of Formulae I, II and 111 are useful intermediates for the final products of Formula IV. The final products of Formula IV, particularly the lfia-bromoand 16a-iodo-17-hydroxyprogesterone 17- acetates, are very active progestational agents which can be used both orally and parenterally. The find application in cyclic therapy where estrogenic and progestational hormones are supplied together or in succession so as to favor re-establishment of normal endometriumovary-anterior pituitary gland relationship in cases of menstrual disturbances. The compounds can further be used in the treatment of animals to produce estrus at the precise period desired, and thereby to control the period of birth of ofisprings in a manner convenient and/or economical for its owner, permitting marketing outside the ordinary seasons.

The l6u-bromoand lfinc-iOdO-fioc-InfithYl-17u-hydIOXY progesterone acylates can be used in form of pills, for example mixed with lactose, glucose, flour and the like, or can be used in aqueous suspension for injectable forms of medications.

The compounds of Formula 1V, moreover, can be used as intermediates in the production of useful antiinflammatory compounds by submitting compounds of Formula IV to fermentation by 11 B-hydroxylating microorganisms, for example Cunninglhzzmella blakesleeana, Curvularia lunatw, species of T richothecium such as Trichothecium roseum, Gongronnella ureolifera, and the like, to obtain the corresponding 11fi,17u-dihydroXy-16abromo-(or iodo-)4-pregnene-3,20-diones which have antiinflammatory activity (particularly topical anti-inflammatory activity) and, thus are compounds useful for ointments, lotions, salves, and the like for the treatment of inflammatory conditions of the skin. The activities of such 11B- derivatives of compound IV are considerably increased by introducing a 9oc-fl11010 group in the wellknown manner and/or by introducing double bonds at C1 2 or C5 7.

Compounds of Formula IV can also be converted to their A -analogs, i.e., 16oz-ha1o-6a-meth3 l-17a-hydroxy-4, 6-pregnadiene-3 ,20-dione 17-acylate by heating compounds of Formula IV, for example with chloranil. Such l6 halo-16a-methyl-17a-hydroxy-4,6-pregnadiene-3,20- dione 17-acylates have enhanced progestational activity and can be used like the compounds of structure IV.

The starting materials 'of structure I, which are novel compounds, are produced as shown in the preparations 1 and 2.

In carrying out the process of the present invention the selected 16a-halo-3B,17a-dihydroxy-6-methyl-5-pregnen-ZO-one in which the halo group is selected from bromine and iodine, dissolved in an organic solvent such as pyridine, carbon tetrachloride, tetrahydrofuran, or the like is reacted with an anhydride of an organic acid or with the chloride or bromide of the acyl group of an organic acid, particularly a hydrocarbon carboxylic acid. Acylation agents thus employed comprise the bromides and chlorides and anhydrides of organic carboxylic acids such as acetic acid, propionic acid, butyric acid, maleic acid, hexanoic acid, heptanoic acid, octanoic acid, decanoic acid, lauric acid, B-cyclopentylpropionic acid, isobutyric acid, benzoic acid, ethylbenzoic acid, phenylacetic acid, phenylpropionic acid, and the like. If a formate is desired, formic acid is used directly. The temperature of the reaction is preferably about room temperature up to C., but a range between 0 and is operable. The esterification proceeds best when an acid catalyst is used, such as toluenesulfonic acid, 2,4-dinitrobenzenesulfonic acid, chlorobenzoic acid, or a very small amount of sulfuric acid. The reaction time depends on the temperature applied and will be between 15 minutes and 1 hour at high temperatures and as long as one day at low temperatures. At room temperature a period between 2 and 8 hours is suflicient. At the termination of the reaction the product is isolated and purified by conventional methods, such as evaporation of the solvents, or pouring the reaction mixture in water to obtain a precipitate, or extraction and evaporation, or crystallization and recrystallization to obtain pure products. If necessary, chromatography can be used.

The selective solvolysis in which the 3,17-diacyloxy EXAMPLE 2 16a-i0d0-313J 7 ct-dihydroxy-6-methyl-5 -pregnen-20-0ne 3,17-diacetate A reaction mixture was prepared containing 0.47 g. of 16a-iodo-3fi,17a-dihydroxy-fi-methyl-5-pregnen-20-one, 3 ml. of carbon tetrachloride, 1 ml. of acetic anhydride, and 7 mg. of 2,4-dinitrobenzenesulfonic acid. This mixture was allowed to stand for 5 hours at 25 C. during which time an intense blue coloration developed, which changed eventually to a light reddish brown color. To this reaction mixture was added 75 ml. of cold water, the mixture was stirred for 1 hour, and extracted with three 50-ml. portions of methylene chloride. The meth ylene chloride portions were combined, dried over anhydrous sodium sulfate and evaporated to give a foamy material which upon recrystallization from aqueous acetone (three times) gave pure 16oc-i0dO-3fi,17oc-dihYdIOXY- 6-methyl-5-pregnen-20-one 3,17-diacetate of melting point 221-225 C. with decomposition, rotation [a1 -69 in chloroform, and having an analysis as follows:

Analysis.Calcd. for C I-1 (556.47): C, 56.11; H, 6.70; I, 22.1. Found: C, 56.19; H, 6.90; I, 22.75.

EXAMPLE 3 1 6 a-bromo-j 3,1 7 oc-dihydr0xy-6-methyl-5 -pregnen-20-0ne 3,17-dibenzozzte In the same manner given in Example 1, l6u-bromo- 3B,I'Ta-dihydroxy-6-methyl-5-pregnen-20-one was reacted in carbon tetrachloride with benzoic acid anhydride in the presence of toluene-sulfonic acid at a temperature between 23 and 26 C. The material which was obtained by evaporation of the solvent was recrystallized repeatedly from acetone and water to give pure l6u-bro mo-SB,17u-dihydroxy-6-methyl-5-pregnene-20-one dibenzoate- EXAMPLE 4 1 6 cz-z'0d0-3 ,8,1 7oz-a'ihydr0xy-6-methyl-5-pregnen-20-one 3,17-dipr0pi0itate 16a-br0m0 or respectively lfioc-iOdO-3/3,17a-dihyd1OXy-6- methyl-S-pregnen-ZO-one 3,17-dihexanoate;

(cl) With octanoic acid anhydride there was obtained l6a-bromoor respectively 16a-iodo-3B,l7a-dihydroxy-6- methyl-5-pregnen-20-one 3,17-dioctanoate;

(e) With decanoic acid anhydride there was obtained 16u-bromoor respectively l6a-iodo-3B,l7a-dihydroxy-6- methyl-5-pregnen-20o'ne 3,17-didecanoate;

(11') With phenylpropionic anhydride there was obtained l6a-bromoor respectively 16a-iodo-3B,17a-dihydroxy-6-methyl-5-pregnen-20-one 3,17-di-(phenylpropionate).

In the same manner given in Example 4, using an acyl halide in pyridine solution with 16a-bromoor respec- The mix- 7 lfia-bIOInO- and 16a-iodo-3B,17a-dihydroxy-6-methyltively 16u-iodo-3/8,l7a-dihydroxy-6-methyl-5-pregnen-20- one, results in the production of the corresponding 16abromoor respectively l6a-iodo-3fi,l7a-dihydroxy-6- methyl-S-pregnen-ZO-one 3,17-diacylates. Thus, cbromoor respectively 1fioz-iOdO-BB,l7a-dihYdI'OXY-6- methyl-S-pregnen-ZO-one Was converted:

(a) With fi-cyclopentylpropionyl chloride to 16a-bromoor respectively 16a-iodo-3f3,17m-dihydroxy-6-methyl-5-pregnen-20-one 3 1 7-di- B-cy-clopentylpropionate) (b) With isobutyryl bromide to l6a-bromoor respectively 1 6m-iodo-3 ,8, 17u-dihydroxy-6methyl-5-pregnen-20- one 3,l7-di(isobutyrate);

(c) With heptanoyl chloride to 16a-bromoor respectively 16a-iodo-3fi,17a-dihydroxy6-methyl-5-pregnen-20- one 3,17-diheptanoate.

EXAMPLE 5 l 6 u-i'odo-S 5,1 7a-dihydroxy-6-methyl-5 -pregnen-20-0ne 17-acetate A solution of 1.6 g. of 16a-iodo-3B,17oc-dihydroxy-6- methyl-S-pregnen-ZO-one 3,17-diacetate in 50 ml. of methanol containing 0.33 ml. of concentrated hydrochloric acid was heated under reflux for 1 hour and then cooled. To the cooled reaction mixture was added an excess of aqueous sodium bicarbonate solution, the mixture was then concentrated at reduced pressure, diluted with water and extracted with three 50 ml. portions of methylene chloride. The methylene chloride portions were combined, washed with Water, dried over anhydrous sodium sulfate and evaporated to give 1.09 g. of material melting at 20l-205 C. after one crystallization from acetone. This material was recrystallized to give pure 16oz-i0d0 35,170; dihydr-oxy-6-methyl-5-pregnen-20-one l7-acetate of melting point 205-207" C. having the following analysis:

I Analysz'.s'.Calcd. for C H IO (514.45): C, 56.03; H, 6.86; I, 24.67. Found: C, 55.97; H,6.99; I, 23.75.

EXAMPLE 6 .1 6 u-bromo- {3,1 7a-dihydn'oxy-6-methyl-5-pregnen-2 O-one 17-acetate In the same manner as shown in Example 5, 2.6 g. of 16m bromo 3,8,17a-dihydroxy-6-methyl-5-pregnen-20- one 3,17-diacetate was selectively solvolyzed in 75 ml. of methanol containing 0.5 ml. of concentrated hydrochloric acid. The mixture was boiled, cooled and the crude material extracted as in Example 5. The crude material was thereupon recrystallized from aqueous acetone to give 1.73 g. of 16u-bromo-3B,l7a-dihydroxy-6-methyl- 5-pregnen-20-one 17-acetate of melting point 202206 C. and having an analysis as follows:

Analysis.-Calcd. for C H BrO (467.46): C, 61.66; H, 7.55; Br, 17.10. Found: C, 61.37; H, 7.59; Br, 17.21.

EXAMPLE 7 16m-br0m0-313,Z 7a-dihydroxy-6-methyl-5-pregnen-20-0ne 17-benzoate In the same manner given in Example 5 two grams of 16a bromo-3 9,17a-dihydroxy-6-methyl-5pregnen-2O-one 3,17-dibenzoate, dissolved in 60 ml. of methanol containing 0.3 ml. of concentnated sulfuric acid, were solvolyzed and .the product obtained by extraction and recrystallized yfrorn aqueous methanol to" give 16a-bromo-3/3,17a-dihydroxy 6-methyl-5-pregnen-ZO-one 17-benzoate.

EXAMPIQE 8 In' the same manner given in'Example 5, two grams of 16 iodo 3B,17 z-dihydroxy-6-methyl-5-pregnen-20-one 3,17 dipropionate in 60 m1. o f'rneth-anol containing 0.4 ml.

nen-20one .17-'propionate.- r

In the same manner illustrated by Example 5, oth'erdi- 'acyla'tes of 16a1h ron1oand 16OL-i0d0-3fi,l lbt-dlhYdfOXY-smethyl-S-pregnene-li,ZO'dione can be selectively. solvolyzed' in an organic solvent such as methanohethanol, or thea like, with hydrochloric acid, sulfuric acid, perchloric acid, hydrobrornic acid, or toluenesulfonic acid catalysis to give the corresponding 17 inonoacylates of l-b romoor respectively 16-iodo-36,17 dihydroxy-6-rnethyl-5-pregnenc 3,20-dione.

Representative"17-rnonoacylates thus obtained; include the 17-propionate, butyrate; -va-lerate,'

hexanoate, -hepta'noate, octanoate,' decanoate, -laurate, .benzoate, -phenylacetate, -phenylprop-ionate, cyclopentylpropionate, -isobutyrate' of 16u-bromo or respectively dione- EXAMPLE 9:

t 1 7.-acetqte V 7 A mixture was prepared containing 0.75 g. of lo x-iodor 3 fi,17oc dihydroxy-6-rnethyl pregnen-20-one l7-acetate in 30ml. of toluene containing 7 ml. of cyclohexanone and This mixture was 0.35 g. of aluminum isopropoxide.

V heatedat reflux for 50 rninuteethencooled, and thereto a was added a 50% aqueous solution of Rochelle :salt (50 m1.) The mixture was then diln'ted with toluene, the org-anic layer was separated and Was washed'with' water,

dried over anhydrous sodium sulfate and evaporated at with benzene and Skellysolve B hexanes andrecrystallized from methanol" to give 1'6a-bromo-6o -methyl-flu hydroxy-4-pregnene-3,20-dione 17-acetate of melting .point 176-183 C. and having the following analysisn In the same mannefi giyeninExamp-le 9, other 17a-. monoacylates of loo-broom and 1-6a-iodo-3B,17 -dihy- Oppenauer oxidation using isoprop'o'xide, tertiary butoxide,

and the like, of aluminum in the 'presence'of acetone,

methyl-ethyl ketongidiethykketone, or preferablycyclm.

hexanone in. anorganic solvent s'uchlas'benzene, toluene,

xylenes, 6r the'like to giveithe corresponding I'Z-acylate ot' la-br'omd. or respectively 16w-iodo'-6-methyl-17e;- I

hydroxyprogesterone. 'Representative compounds thus obtained and belonging to'this class include'the 17-Propionate, 17-butyrate,; 17-valerate, l7-hexanoate, V tanoate, l7-octanoate, '17-decano'ate,. 17-laurate', .1'7 isohutyrate, 1'7- ebenz'oate, 17 -'cyclopientylpropionate, 17- phenylacetate, l7-phenylpropionate', and the like of 1600-;

bromoor respectively 16a-iodo 6a-methyl47ot hydro reduced pressure to give {an oil: which was chromato- V graphed over'100 g. of Plo'risil anhydrousmagnesium silicate. Fractions were obtained by elution with mixtures of acetone-Skellysolve B hexanes, and the fractiqnscom anes were combined and evaporated to give 0.55 g. or

solid material which was re'chromatogrlaphed over 100 of Florisil anhydrous magnesium silicate, using linear gradient elution (the solvent system consisted of 2' 1, ,of

20% acetone80% Skelly-solve B and 21. 'of Skellysolve V i B hexanes). 7

- tions 14-17 of these'200 ml. fractions were combined and Fractions of 200 ml. were collected. Fracevaporated tofgive 0.28 g. of material which was redissolved in 1:1 petroleum ether-benzene mixturefand chromatographed over 12.5 g; of n'eutral, deactivated alumina ther elution with benzene gave 0.19 g. ofan oil which was crystallized from aqueous methanol to give 75 mg. of 1611 -iodo' 17DL- hydroxy-6u-rnethyl-4-pregnene-3,20sdione 1 7- acetate of melting point 176 179 C. with'dec rnpo'sition and having an analysis as follows:

AIIalySiS.-C2ilCd;'f0I' Cal-1 (512.41); C, 56.25; H, 6.49;]1, 24.7 7. FQLIHGZ C, 56.45; H, 6.39; 1,2431.

.1: 1 EXA LE IO V In the samenianner given in Example 9, 16a'-,brorno sisting of 10 to 15% acetone, balance oS kellysolye'B hex- The products of this invent-ion can alsobemade accordv I ing to .the process illustr-ateld'below by the synthesis of 16o: bromo 6amethy1 17a-hydroxy-4-pregnene53,20

dione 17'-aceta-te inEx-ample 11; 7

EXAM LE 11 I dioi e acetate 3A solution of 3.77 of .16h,l7q-oxido 6a methyl-4- pregnene-3,-20-dione' in 60 inhof acetic acid was treated 'with4ml. of 32% hydrogen vbl'OlTlldfilH acetic acid for /2' 5 hour at- C. The 'mixture'was diluted to 500ml. with ice water ;to give 1Gfi-hromo-l7a hydroxy-6wmethyl+4 -pregnene-3,20-dione as a solid but gummyproduct which;-

was; collected andwashed with Water,

7 A 4 gfsarnple of the crude1fi-bromo-l7a-hydroxy oa; rnethyl-4-pregn ene-3,ZQ-dione in 160 ml. of methanol was refluxedffor 1 hour with 2 got RaneyThickel; .The re-' action mixture :was thenJ-cooled' and filtered. I The filtrate" -was evaporated, redissolved in acetone and 'chrornato- '45 graphed over 250 g. of Florisil magnesium-silicate using 7 point184-I-202 C. andlhefollowing analysis:

(British 2). Elution with the same solvent mixture (pef troleum ether-benzene) gave traces of oils and then for:

' ,35 17a-dihydroxy-6 rnethyl-S regnen-ZO one 17 -acetate "was oxidized with alum-inum 'isopropoxide ii; a c'ycl-ohex- "anone-t-oluene solution .atreflux temperature;

tained product was thereupon isolated bychromatography nal se-cared. for C H O Br (423;41): Br, 18.87.

Fouridz'Br, 18.19. I

A suspension of 0.35 g. of"16zbromo 6ainethyl-17a- 1 hydroxy-4:pregnene-3,ZO-dioriein 2.7 ml. of carbon ltetrachloride and 0.9 ml. of acetic anhydride containing 5. mg. I of 2,4 -dinitrobenzenesulfonic acid was stirred briefly to dissolve; The mixture was'then allowed. to stand for 5 hours at 25,C. Thereafter 20 ml. of aqueous saturated V sodiumfbicarbonate solution was added andthereupon methylene chloride; The organiclayer.Which separated I was washed with water, dried, over anhydroussodiurn sulj fate, and evaporated to a foam. A' solution of the foam 1 in l3,ml..;of methanol containing 0.09 m1. ofconcen trated hydrochloric, acid was refluxed for 1 lioing' therr .coo1e'd, neutra lized with sodium bicarbonate" solution,

diluted with water and extractedwith methylene chloride. 7

The organic extractwas dried over anhydrous magnesium sulfate," concentrated to dryness, and chromatographed' "over 50 g. of Florisil magnesiumsilicate. iThepeak'frac-f T tion eluted, with 1Q15%. acetone. in Skellysolve B' hexanes was crystallized .fromflaqueous acetone to. give.

17-hep- I '7 gradient elution consisting of acetone. and Skellysolve B1 hexanes containing'from 0% acetone to 30% acetone'in skellysolve B:hexanesl Crystallization of a'peaktfraction j -of :ac etone-Skellysolve B 'hexa'nes'and recrystallization from aqueous methanol'gave 0.15 g. of 16u-b'ron1o-17w hydroxy 6a -methyl 4-pregnene-3,20-dione of melting,

nene3,20-dione 17 acetate ofrnelting'point.176%183}? C; 4

A mixture of 1 g. of 16a-bromo-6u-methyl-17a-hydroxy-4-pregnene-3,20-dione acetate and 1 g. of chloranil in 100 ml. of t-amyl alcohol is stirred and heated to reflux for about 6 hours. (Completeness of the reaction was determined by testing the ultraviolet absorption at about 240 m Disappearance of the absorption indicates the completeness of the reaction.) The reaction mixture was then cooled and filtered and the filtrate evaporated in vacuo. The residue was partitioned between methylene chloride and water; the methylene chloride layer was then separated, washed with water, dried over anhydrous magnesium sulfate and evaporated until a solid residue was obtained. This residue was crystallized three times from aqueous methanol to give pure 16a-bromo-6'- methyl-17a-hydroxy-4,6-pregnadiene-3,ZO-dione acetate.

In the same manner given in Example 12, reacting 16oziodo-6a-methyl-17a-hydroxy-4-pregnene-3,20 dione acetate with chloranil in t-amyl alcohol gave 16oc-iOdQ-6- methyl-17u-hydroxy-4,6-pregnadiene-3,20 dione 17 acetate.

Reacting in the manner disclosed in Example 12 other hydrocarbon carboxylic acid esters of 16u-bromoand 16m-iodo-6a-methyl-17u-hydroxy-4-pregnene-3,20 dione with chlora'nil in t-amyl alcohol gave the corresponding 17-acylates of la-bromoand 16a'a-iodo-6-methyl-17ahydroxy-4,6-pregnadiene-3,ZO-dione. Representative esters thus obtained include the 17-propionate, 17-butyrate, 17-valerate, 17-hexanoate, 17 heptanoate, 17 octanoate, 17-decanoate, 17-laurate, l7-o-ethylbenzoate, 17-p-ethylbenzoate, 17 phenylacetate, 17-phenylpropionate, 17- cyclopentylpropionate, and the like, of 16m-bromo-6- methyl-17u-hydroxy-4,6-pregnadiene-3,20-dione and 16aiodo-6-methyl-17u-hydroxy-4,6-pregnadiene-3,20-dione.

Submitting to fermentation by Cunninghamella blakesleena or Curvularia lzmzzta 16a-bromoand l6cc-i0dO-5- methyl-17a-hydroxy-4,6 pregnadiene-3,20-dione 17-acylates results in the 17-acylates of 16a-bromoand 16u-iodo- 6-methyl-1 15,17u-dihydroxy 4,6 pregnadiene-3,2O diones. Treatment of these compounds with calcium oxide and iodine, and subsequently with potassium acetate gave 16oc-b10m0- and-16a-iodo-6-methyl-1 1fi,1'7u,'21-trihydroxy- 4,6-pregnadiene-3,20-dione 17, 21-diacylates, which can be hydrolyzed with sodium bicarbonate in methanol in a nitrogen atmosphere to give the free alcohols, lfiwbromo- 11,6,17oz,21-t1ihydroxy-4,6-pregnadiene 3,20 dione and 16a-iodo-11fi,17u,21-trihydroxy 4,6 pregnadiene 3,20- dione, having high anti-inflammatory activity.

I claim:

1. A 16a-halo-6u-methyl-l7aacyloxy 4 pregnene of the formula:

CH3 --OAc ]-Hal wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms and wherein Hal is a halogen atom selected from the group consisting of bromine and iodine.

2. 16a-bromo-6u-methyl 17oz hydroXy-4 pregnene- 3,20-dione 17-acetate.

3. 16a-iodo-6u-methyl-17a-hydroxy-4-pregnene 3,20- dione 17-acetate.

. 10 4. A 16a-ha1o-6-methy1-17u-acyloxy-4,6 pregnadiene of the formula:

wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms and wherein Hal is a halogen atom selected from the group consisting of bromine and iodine.

5. 16a-bromo-6-methyl-17a-hydroXy-4,6 pregnadiene- 3,20-dione 17-acetate.

6. 16a-iodo-6-methyl-17u hydroxy 4,6 pregnadiene- 3,20-dione 17-acetate.

7. l6a-halo-3 8,17a-dihydroxy-6 methyl 5 pregnen- 20-one, wherein the halogen is selected from the group consisting of bromine and iodine.

8. l6oc-bI0H10-3 B,17a-dihydroxy-6-methyl 5 pregnen- 20-one.

9. 16a-iodo-313,17u-dihydroXy-6 methyl 5 V pregnen- ZO-one.

10. 16a-ha1o-3B,17a-dihydroxy-6 methyl 5 pregnen- ZOeOHE 3,8,17a-diacylates of the formula:

wherein Hal is a halogen atom selected from the group consisting of bromine and iodine and Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

1'1. bromo 813,170: dihyd-roxy 6 methyl- 5-pregnen-20-one 3B,l7a-diacetate.

12. 16oz iodo 3,3,: dihydroxy 6 methyl 5 pregnen-ZO-one '3,B,17u-diacetate.

.13. 160a halo 35, 170 dihydroxy 6 methyl -5- pregnen-20-one l-7a-acy-lates of the formula:

wherein Hal is a halogen atom selected from the group consisting of bromine and iodine and Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 canbon atoms, inclusive.

'14. 16a bromo 3fi,l7a dihydroxy 6 methyl 5- pregnen-ZO-one 17a-acetate.

15. 16a iodo 319,17a-dihydroxy-6-methy1 5-pregnen- 20-one Hot-acetate.

16. A process for the production of 'aloa-halo'awhethyl- 1'7a-acyloxypregnane of the formula:

7 7 =0 -OAc V VI-Hal "wherein Acris the acyl radical of an' or ganic car-boxylic acid containing from 1 to'12 carbon atoms and wherein 16oc-halo-6cc-methyll7gz-hydroxy 4 pregnenej- 3,20-dione 1-7-acylate. I

-1'7.'A' process for the production oft l6 oi lar onio-6ul-p methyl 17a hydroxy 4 7 pregnene 3, 2 0 dione 17- ace,ta-te,- whichrcompris'esi f-treating 16 bromfcn- 3B,

170: dihydroxy 6 methyl 5 pregnn 2. e one with acetic anhydride to obtain li6oc-brom0-3 ,l7a-dihydnoxy+ 6-methyl-5-pregnen- 20-one 3,17-diaccta-te; selectively sol:

Hal is a halogen atom selected fromthe group consisting of bromine and iodine which comprises: treating 3. 16a

halo-318,-17a-dihydroxy-6-inethyh5 pregnen 20 one, wherein the halogen atom is defined as above, with an acylatingtagent selected ifr-oni the group consisting of a'cyl bromides; acyl chlorides and organic carboxylic acid boxylic acid are defined as hereinbefore, to 'obtain the corresponding l6a-halo 3fl,l7adiacycloxy 6 amethy-l 5- pregnen-20=one, wherein acyl and the halogen is defined as above;.selectively solvolyzing this 'di-acylate with an alkanol having from 1 to 4 carbon atoms, inclusive, in or the presence of a'stroiig acid to'obt ain the corresponding 1'7-monoacy1ate and oxidizing the resulting 17,-rnonoacyl ate with a reagent selected from the group consisting of nene-3,20'-dione l7-aceta-te o c I r t V V 18. Aprocess for the production Oflficc-iO d 0-60crn1:efi1yl-" V 17 a-hydroxy-4v-pregnene-3,ZO-dione 17,-acetate which comprises: treating ls6a-iodo3fi, l-7 oi dihydroxy 6 rnethylsS pregnen-20 one with acetic :anhydride tolobtain' '16pg-lQdO- '3,3,l7a-dihydroxy-6-mcthyL5-pregnenF20+one ,3,:17 1sces tate; selectively solvolyzing the obtained 3jl-7-diacetate in methanol with hyd 'echloricnaeid to'obtain' 16a-iodo-3B; -di ydI9 ye y -5-Preg n-20 cn .17- a e d;

volyz ing the-obtained -3, l7-diace tate in methanol with it hydrochloric acid to obtainl6 a brorno-313,17a9dihydroary- 6-methyl-5-pregnen-20-one, 17-acetate "and 'OXldiZiHgjEfhQ 1 S-hydroxyl with aluminum isopropoxide and asketoneto" hydroxy 4 -i preg- V oxidizing the 3-hydrox5rl with aluminumisopropoxide and anhydnides, wherein the acyl group and the organic car- 7 aluminum isopropoxide and aluminum tertiary butoxide V in the presence of a ketone to obtain theconr esgonding a ketone to obtain 16o; iodo l 6d-methylel7ggehydroxy k pregnen-3,2O- dione lT-acetate. j r r References Cited the Examiner Syhora: Coll. Czech. Chem. Comm., vdlZfiQ'April' Syhora: Coll. Czech. Chem Cornm vol; 2-8 ,*March g GOTIS, Primary Examined 

1. A 16A-HALO-6A-METHYL-17A-ACYLOXY-4-PEGNENE OF THE FORMULA: 